Project Summary. The genetic basis of age-related hearing loss (presbycusis) is poorly understood because of the extreme difficulty in studying such a late-onset genetically complex disorder. The laboratory mouse provides promising models for studying human presbycusis because age-related hearing loss (AHL) is common in inbred mouse strains and mice are more amenable to genetic analyses. We have shown that a gene on Chromosome 10 (ahl) is a major susceptibility factor for AHL in more than 10 inbred strains of mice and that three other genes (ah!2, ah!4, and a/7/8) and a mitochondrial mutation also contribute to hearing loss in particular inbred strains. We hypothesize that the genetic predisposition and the pathophysiological pathways involved in the mouse are also involved in humans and that further genetic and pathological studies of AHL in mice will add significantly to our understanding of presbycusis in humans. Our specific aims are to (1) formally test the hypothesis that a Cdh23 variant is responsible for the hearing loss attributed to the ahl locus by gene "knock-in" experiments and analyze the molecular mechanisms and interactions with other genes that underlie its effect on AHL;(2) refine the genetic map positions and attempt to identify the genes responsible for a/7/2, ah!4, and a/7/8;and (3) characterize the inner ear pathologies associated with the AHL loci and inbred mouse strains developed in Aims 1 and 2. The long-term objectives of this research are to identify the major genetic factors and molecular mechanisms that influence predisposition, time of onset, and pathological presentation of AHL in inbred strains of mice as models for human presbycusis. Relevance to public health. Presbycusis is the most common sensory deficit in human populations; about 1 in 3 adults older than 60 suffer from a significant hearing loss. The proposed genetic and pathological studies of age-related hearing loss in mice will provide important insights to improve our understanding of the major genetic factors and molecular pathways that influence human presbycusis, which could contribute to the development of diagnostics, preventive interventions, and therapies.